Heb nachtdienst, dus zoek het eea even op. Misschien helpt dit nog andere dames: Ovulation induction with clomiphene citrate Ovulation induction with clomiphene citrate Authors Emre Seli, MD Aydin Arici, MD Section Editor Robert L Barbieri, MD Deputy Editor Kathryn A Martin, MD Disclosures All topics are updated as new evidence becomes available and our peer review process is complete. Literature review current through: feb 2012. | This topic last updated: okt 7, 2011. INTRODUCTION Clomiphene citrate has been the most widely used treatment for fertility enhancement for the past 40 years. Clomiphene was a revolutionary advance in reproductive medicine and quickly became popular for induction of ovulation because of its ease of administration and minimal side effects. Ironically, it was initially synthesized as a synthetic estrogen for possible use as a contraceptive. The pharmacology, indications, and administration of clomiphene citrate will be reviewed here. Other drugs for induction of ovulation are discussed elsewhere. (See "Overview of ovulation induction" and "Metformin for treatment of the polycystic ovary syndrome" and "Strategies for improving the efficacy of clomiphene induction of ovulation".) PHARMACOLOGY Clomiphene is a triphenylethylene derivative distantly related to diethylstilbestrol. It acts as a selective estrogen receptor modulator, similar to tamoxifen and raloxifene. All three drugs are competitive inhibitors of estrogen binding to estrogen receptors and have mixed agonist and antagonist activity depending upon the target tissue. (See "Mechanisms of action of selective estrogen receptor modulators".) The commercially available form of clomiphene is the dihydrogen citrate salt (clomiphene citrate). It contains two stereoisomers: zu-clomiphene (38 percent) and en-clomiphene (62 percent), which were originally called the cis-isomer and trans-isomer, respectively. En-clomiphene is cleared rapidly, while zu-clomiphene has a long half-life. The two clomiphene isomers have mixed estrogenic and antiestrogenic effects that vary among species. Zu-clomiphene appears to have greater estrogenic activity than en-clomiphene. 14C-labeled clomiphene citrate is absorbed by the gastrointestinal tract. Fifty percent of the oral dose is excreted after five days, but radioactivity from labeled clomiphene appears in the feces up to six weeks after administration. However, the pharmacologic effect of clomiphene citrate is brief. MECHANISMS OF ACTION Clomiphene exerts its major effects on the hypothalamus, pituitary, ovary, and uterus. Hypothalamus and pituitary Most evidence suggests that the primary site of clomiphene action is the hypothalamus, where it appears to bind to hypothalamic estrogen receptors, thereby blocking the negative feedback effect of circulating endogenous estrogen. Elevated plasma concentrations of follicle stimulating hormone (FSH) and luteinizing hormone (LH) result from clomiphene treatment. When clomiphene is administered to normally cycling women, LH pulse frequency (but not amplitude) increases, suggesting an increase in hypothalamic gonadotropin-releasing hormone (GnRH) pulse frequency [1]. In women with polycystic ovary syndrome, who have a high frequency pattern of LH pulses at baseline, the administration of clomiphene citrate produces an increase in LH pulse amplitude, as well as an increase in the daily plasma concentrations of LH and FSH [2]. (See "Physiology of gonadotropin-releasing hormone".) In vitro data suggest that clomiphene citrate also has a pituitary site of action where it causes an increase in the gonadotropin response to GnRH [3]. Ovary The ovarian actions of clomiphene are for the most part secondary to the effects of elevated FSH and LH on ovarian follicular development. (See "Physiology of the normal menstrual cycle".) Clomiphene is an estrogen agonist in the absence of estrogen, thereby enhancing FSH stimulation of LH receptors in granulosa cells. Direct effects of clomiphene on the ovary are not well understood but probably exist. As an example, clomiphene may activate aromatase, the enzyme that increases conversion of androstenedione to estrogen. Uterus and cervix Clomiphene acts primarily as an antiestrogen in the uterus, cervix, and vagina. The following findings have been noted, which may at least partially explain the low pregnancy rates observed in clomiphene-induced ovulatory cycles: